Age-related macular degeneration (AMD) is the most common cause of acquired visual impairment in people over the age 60. AMD is considered to be a multifactorial disorder associated both with environmental and genetic factors. Currently, no reliable treatment options are available for AMD with the exception of the laser photocoagulation therapy that can be applied to a small fraction of patients with short-term effects. In spite of great successes in deciphering the genetic cause of Mendelian retinal diseases, almost nothing is currently known about the genetic determinants of AMD. The underlying hypothesis of this application is that increased susceptibility to AMD in individual cases results from a combination of defects in many genes, i.e., from specific genotype(s). This proposal, from a newly established laboratory of genetics of eye diseases, is directed towards deciphering the genetic cause of AMD by a combination of several approaches. We plan to: (1) Substantially increase the cohorts of patients and controls to be screened for DNA variants (to about 2000 samples each), including both sporadic and familial cases; (2) Utilize semi-automated, high-throughput screening methods, including the allele-specific microarrays for genotyping; (3) Employ complementary methods of allelic association analyses of the data, such as the case-control association study and the transmission disequilibrium test (TDT); (4) Correlate the large numbers of derived genotypes with phenotypic variation in AMD by statistical analyses. Our preliminary experience indicates that progress in this area of research can only be achieved if a project includes all the components listed above. Identification of genes, alleles, and genotypes underlying the AMD complex trait and understanding how these defects contribute to the development of macular degeneration has the potential to improve the quality of life of the affected individuals. Further, it will enable the accurate identification of at-risk individuals before they develop the disorder, and has the potential to modify or prevent the devastating visual consequences of this disorder in future generations.